Semicarbazones and thiosemicarbazones of 17alpha-substituted 3-keto-steroids

ABSTRACT

13-ALKYL-17X-SUBSTITUTED - 17 - HYDROXYGON-4-EN-3-ONE, SEMICARBAXONES AND THIOSEMICARBAZONES, $4,6,8(14),9 AND 11 DEHYDRO ANALOGS, AND D-HOMO ANALOGS THEREOF, OPTIONALLY SUBSTITUTED BY METHYL AT POSTIONS 1,2,4,6,7 AND 11, ALKANOYL AT POSTION 17, BY ALKYL, ARYL, ARYLALKYL AND ALKYLARYL IN THE SEMICARBAZONE OR THIOSEMICARBAZONE GROUP, AND BY A 17X-ALKYL GROUP OR BY METHYL OR HAOLGEN IN A 17X-ETHYNYL GROUP (I) ARE PROVIDED BY CONDENSING THE CORRESPONDING 3-KETOSTEROID (II) WITH THE CORRESPONDING SEMICARBAZIDE OR THIOSEMICARBAZIDE (III). COMPOUNDS (I) ARE PHARMACOLOGICALLY ACTIVE IN WARM BLOODED LOWER ANIMALS AS BRONOCHODILATORS AND AS ANTI-INFLAMMATORY AGENTS.

United States Patent 3,642,842 SEMICARBAZONES AND THIOSEMICARBAZONES 0F 170t-SUBSTITUTED S-KETO-STEROIDS Albert J. Begany, Perkiomenville, Kurt W. Ledig, Philadelphia, Donald W. Oliver, West Chester, and Gerhard R. Wendt, Havertowu, Pa., assiguors to American Home Products Corporation, New York, N.Y. No Drawing. Filed Dec. 23, 1968, Ser. No. 786,373 Int. Cl. C07c 169/20 US. Cl. 260-3975 11 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel steroidal compounds with valuable pharmacological properties. More particularly, it is concerned with semicarbazones and thiosemicarbazones of 17oz substituted-3-ketosteroids which exhibit bronchodilating and anti-inflammatory activity in standard pharmacological tests when administered to warm blooded laboratory animals.

DESCRIPTION OF THE INVENTION The compounds contemplated by this invention are those of Formula I:

wherein X is O or S; Y is alkyl or ---CECR wherein R is hydrogen, methyl, chloro, bromo or fiuoro; R is alkyl; R is hydrogen or alkanoyl; R R R R, R and R are hydrogen or methyl; R is hydrogen, alkyl, monocarbocyclic aryl, monocarbocyclic arylalkyl or alkylmonocarbocyclic aryl; n is 1 or 2; the broken lines indicate a single or double bond and said alkyl and alkanoyl substituents contain from about 1 to about 7 carbon atoms.

Special mention is made of a number of particularly important embodiments of this invention: These are the gon-4-ene compounds of Formula I wherein:

X is S; Y is CECH, R is ethyl, R R R IR R R R R and R are hydrogen and n is 1, i.e., 13-ethyl- 17a e'thynyl 17 hydroXygon-4-en-3-one, thiosemicarbazone, and especially the l-enantiomer thereof, substantially free of the d-enantiomer;

X is S, Y is --CECH, IR is methyl, R R R R R R", R and R are hydrogen and n is 1, i.e., Hot-ethynyl- 17-hydroxyestr-4-en-3-one, thiosemicarbazone;

X is S; Y is CECC1, R is ethyl, R R R R R 3,642,842 Patented Feb. 15, 1972 R R and R are hydrogen and n is 1, i.e., 17oz-Chl0l0- ethynyl 13 ethyl-l7-hydroxygon-4-en-3-one, thiosemicarbazone;

X is S; Y is CECC1, R and R are ethyl, R R R R R, R and R are hydrogen and n is 1, i.e., 17achloroethynyl 13 ethyl-17-hydroxygon-4-en-3-one, (4- ethyl-3-thiosemicarbazone) X is S, Y is -CECH, R and R are ethyl, R R R R R R and R are hydrogen and n is 1, i.e., l3- ethyl-l7a-ethynyl-17-hydroXygon-4-en-3-one, (4 ethyl- 3-thiosemicarbazone) X is S; Y and R are ethyl; (R R R R R, R", R and R are hydrogen and n is l, i.e., 13,17a-diethyll7-hydroxygon-4-en-3-one, thiosemicarbazone; and X is O; Y is -CECH, R is ethyl, R R R R R R R and R are hydrogen and n is l, i.e., l7-hydroXy-17aethynylestra-4-en-3-one, semicarbazone.

X is S; Y is CECH; R is methyl; R R R R R, R and R are hydrogen; R is ethyl and n is 1, i.e., 17aethynyl-l7-hydroxyestr-4-en-3-one, (4 ethyl-3-thiosemicarbazone); and

X is S; Y is -CECH; R is methyl, R R R \R R R and R are hydrogen; R is methyl and n is 1, i.e., 17ozethynyl 17 hydroXyestr-4-en-3-one, (4-methyl-3-thiosemicarbazone).

With reference to Formula I and the definitions of substituents, a preferred family of analogs of the A compounds are the A the A4941, the A the A and the M dehydro analogs thereof. The term alkyl contemplates hydrocarbon substituents of from about 1 to about 7 carbon atoms, straight chain and branched, illustrative members of which are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 2- methyl-pentyl, n-hexyl, n-heptyl, and the like. The term alkanoyl contemplates hydrocarbon acyl radicals of from about 1 to about 7 carbon atoms, the hydrocarbon portion of which may be straight chain and branched, illustrative members of which are formyl, acetyl, n-propionyl, n-butyryl, i-butyryl, n-pentanoyl, n-hexanoyl, n-heptanoyl, and the like. When n is 1 ring D of the normal series of steroids is contemplated, when n is 2 there is contemplated the D-homo series. The terms monocarbocyclic aryl and alkyl monocarbocyclic aryl contemplates the phenyl ringand phenyl substituted with from about 1 to about 3 alkyl groups as above defined, particularly the tolyl and xylyl groups. Monocarbocyclic arylalkyl contemplates phenyl-substituted alkyl of from 1 to 7 carbon atoms, illustratively, benzyl, wphenylethyl, and the like. In a preferred family of compounds of Formula I, R is C to 0, alkyl, R is hydrogen or acetyl, R is hydrogen or chloro, R R R R, R and R are hydrogen, and R is hydrogen or C 0 alkyl, preferably ethyl.

In the product (I) of a total synthesis which has not included a suitable resolution stage the compounds of the invention will be present as racemates. Using a convention approved by Fieser and Fieser, Steroids, p. 336 (1959), the compounds designated as the d-forms are the enantiomers corresponding in configuration to that of the natural hormone estrone. The corresponding enantiomorphs are consequently designated the l-forms and the racemates the dl-forms. Racemates will be depicted by structural formulas which show only the enanthiomorphs of the d-configuration. A preferred family of compounds of Formula I comprises the l-enantiomers, substantially free of the d-enantiomers. Although all in common, the dl-, the dand the l-forms, possess potent bronchodilating properties, the l-forms are surprisingly devoid of progestational activity. Because of this they are useful in instances wherein hormonal effects are not desired.

The compounds of Formula I hereinabove are prepared by a process comprsiing condensing a S-keto steroid of Formula II:

wherein R, R R R R R R R R and n are as hereinabove defined, with a semicarbazide of Formula III:

R HN-ii-NHNH2 III wherein X and R are as hereinabove defined until formation of a semicarbazone compound of Formula I is substantially complete and recovering said compound.

The conditions under which the said process is carried out are not particularly critical. The 3-ketosteroid (II) can be reacted with the stoichiometrical amount or an excess of the semicarbazide (III) in an inert diluent, e.g., a lower alkanol, e.g., methanol or ethanol (or acetic acid with thiosemicarbazide in some cases, see examples), or even in mixtures thereof at temperatures of from about 10 C. to about the reflux temperature of the mixturesteam bath temperatures are especially useful. Depending generally on the nature of the reactants and the temperature, the condensation is substantially complete in from about 10 minutes to about 24 hours. The products (I) can be recovered by any conventional means, such as by adding water, and separating and recrystallizing the liberated product, or by evaporating the solvent leaving the product as a residue. In one manner of proceeding, 0.5 part by weight of 3-ketosteroid (II) and 0.3 part by weight of semicarbazide (III) are suspended in 10 parts by volume of glacial acetic acid and the mixture is heated to reflux for 10 minutes. Cooling and diluting with water causes the product to separate. The product is filtered off and, if desired, purified by recrystallization, e.g., from alcohol and water. This general technique and modifications will be exemplified in detail hereinafter.

The starting materials of Formula II are 3-ketosteroids which can be obtained by means known to those skilled in the art. Reference is made, for example, to the description of the total synthesis of 17a-substituted gon-3- ones in H. Smith, G. A. Hughes, G. H. Douglas, G. R. Wendt, G. C. Buzby, Jr., R. A. Edgren, J. Fisher, T. Foell, B. Gadsby, D. Hartley, D, Herbst, A. B. A. Jansen, K. Ledig, B. I. McLoughlin, I. McMenamin, T. W. Pattison, P. C. Phillips, R. Rees, J. Siddal, J. Siuda, L. L. Smith, I. Tokolics and D. H. P. Watson, J. Chem. Soc., 1964, 4472-4492.

Illustrative of important starting materials of Formula II are:

d-17a-ethynyl-17-hydroxyestra-4,9-1 1-trien-3-one, acetate (Netherlands patent application No. 66. 10,741);

d-17oc chloroethynyl 17 hydroxyestra 4,9,11- trien-3-one [Compt. Rend. 260, 4545 (1965)];

d-1u,7a dimethyl-17a-ethynyl-17-hydroxyestr-4-en-3- one (ICF Vol. 10, Netherlands Week No. 145, Basic 18,863);

d-17a ethynyl 17 hydroxy-4-methylestr-4-en-3-one (J. Chem. Soc. 1962, p. 1091);

dl-l7a-ethynyl-17-hydroxyestra 4,8(l4)-dien-3-one LI. Org. Chem., 31, 3780 (1966)];

d-17a-ethynyl-17-hydroxyestra-4,9-dien-3-one [1. Am. Chem. Soc., 82, 2402 (1960)];

d 1704 ethynyl 17 hydroxyestr 4,9,11 trien-3-one [Compt. Rend. 260, 4545 (1965) d-17a-ethynyl-17-hydroxy llfl methylestr-4-en-3-one (according to the procedures of US. 3,299,102); and, in addition,

d-17a-ethynyl-17-hydr0xyestr-4-en-3-one;

l-l3-ethyl-17a-ethynyl-17-hydroxygon-4-en-3-one;

dl-17oz-chloroethynyl-13-ethyl 17 hydroxygon-4-en-3- one;

dl-l3-ethyl-17a-ethynyl-17-hydroxygon-4-en-3-one;

d-1Wat-chloroethynyl-17-hydroxyestra-4,9-dien-3-one;

dl-l3-ethyl-17u ethynyl-l7-hydroxygon 4 en-3-oneacetate;

dl-13 ethyl-17ot-ethynyl-17-hydroxygon-4-en-3-one, nheptanoate;

dl-17aa-chloroethynyl-13-ethy1 17a hydroxy D homogon-4-en-3-one;

all-17 3 hydroxy-13-n-propyl-17-(1-propynyl)gona-4,9- dien-3-one;

dl-l3-ethyl 178.0: ethynyl-17a-hydroxy-D-homogon-4- en-3-one;

dl-l3-ethyl-17a-ethynyl-17-hydroxygona-4,8(14) dien- 3-one;

dl-13-ethyl-17a-ethynyl-17-hydroxy 6oz methylgon-4- en-3-one;

dl-13 ethyl-17a-ethynyl-l7-hydroxygon-4,6-dien-3-one, acetate;

l-17a-chloroethynyl-13-ethyl 17 hydroxygon-4-en-3- one;

dl-17a-ethynyl-17-hydroxyester-4-en-3-one, acetate;

dl-17a-ethynyl-17-hydroxy-13-n-propylgona 4,9 dien- 3-one; and

dl-l3-n-butyl-17a-ethynyl-17-hydroxygon-4-en-3-one.

The semicarbazides of Formula III are items of commerce or can be prepared in known ways.

Illustrative of the important starting materials of Formula III are: thiosemicarbazide; 4-methylthiosemicarbazide; 4-ethylthiosemicarbazide; and 4-butylthiosemicarbazide, all of which are commercially available; and 4- heptylthiosemicarbazide; 4-phenylthiosemicarbazide; 4- benzylthiosemicarbazide; and

4a-phenylethylthiosemicarbazide, which can be prepared according to J. Chem. Soc., 1927, p. 2529; and 4-otolylthiosemicarbazide and 4 p tolylthiosemicarbazide, both of which can be prepared according to Ann., 434, 289 (1923). The corresponding semicarbazides are likewise commercially available or easily prepared.

As is mentioned hereinabove, the instant compounds of Formula I in standard pharmacological tests have bronchodilating and anti-inflammatory activity. More particularly, when administered intraperitoneally to guinea pigs, compounds of Formula I are found to protect the animals against respiratory difliculties (bronchoconstriction) induced by a histamine mist. When administered perorally to rats, compounds of Formula I are found to inhibit experimentally induced inflammatory swellings, specifically the edema induced in the rats right hind paw by injection of a 1% carrageenin solution in saline into the tissue thereof. The instant compounds, therefore, are deemed to possess utility in experimental and comparative pharmacology and are of value to treat conditions in animals, such as valuable domestic animals, and in laboratory animals, such as mice, rats, guinea pigs and the like, responsive to treatment with bronchodilators, such as the need to relieve bronchial spasm, and with anti-inflammatory agents, such as the need to prevent edemae.

When used for these pharmacologically important purposes, the compounds of Formula I of this invention may be administered either alone or in combination with other pharmacologically-active ingredients. Whether singly or in combination, they may be used in the form of solid compositions for oral administration combined, if desired, with extenders or carriers that are relatively non-toxic or inert. They may be put into tablet, capsule or powder form.

They may be mixed with animal foodstuffs. On the other hand, they may be administered in liquid form as a suspension or solution in a vehicle for parenteral use. By way of illustration pharmacological action as bronchodilators in guinea pigs has been demonstrated when compounds of this invention have been administered at dosages of and mg./kg., i.p.; and as anti-inflammatory agents in rats at a dosage of 50 mg./kg., p.o.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the scope and spirit thereof.

EXAMPLE 1 d-17u-ethynyl-17-hydroxyestr-4-en-3-one, thiosemicarbazone A solution of 894 mg. of d-l7ot-ethynyl-17-hydroxyestr- 4-en-3-0ne, 273 mg. of thiosemicarbazide, and 50 m1. of alcohol is heated on a steam bath for 3 hours while evaporating 25 ml. of the solvent. After the addition of 10 m1. of acetic acid, the reaction mixture is refluxed another hour, diluted with water, and the precipitate filtered to give 900 mg. of the title compound; M.P. 150- 160 C.

Analysis.--Found (percent): C, 67.89; H, 7.85; N, 10.75; S, 8.54, C H N OS requires (percent): C, 67.88; H, 7.86; N, 11.30; S, 8.63.

EXAMPLE 2 l-13-ethyl-17a-ethynyl-17-hydroxygon-4-en-3-one thiosemicarbazone A suspension of 180 mg. of thiosemicarbazide, 620 mg. of l-l3-ethyl-l7a-ethynyl-17-hydroxygon-4-en-3-one, 10 ml. of alcohol and 10 ml. of acetic acid is heated on the steam bath for 1 hour. On addition of water, a gum is obtained which is crystallized from alcohol and 'water to give 500 mg. of the title compound; M.P. 160170 C.

Analysis.--Found (percent): C, 68.50; H, 8.13; N, 10.87; S, 8.28. C H N OS requires (percent): C, 68.54; H, 8.11; N, 10.90; S, 8.3.

EXAMPLE 3 dl-17u-chloroethynyl-l3-ethyl-17-hydroxygon-4-en-3-one, thiosemicarbazone A solution of 0.5 g. of dl-17a-chloroethynyl-13-ethyl- 17-hydroxygon-4-en-3-one and 0.3 g. of thiosemicarbazide in 10 ml. of glacial acetic acid is heated to reflux for 10 minutes. A precipitate forms on cooling and dilution with Water. The product is filtered, leached once with hot water, filtered again and dried to obtain 0.3 g. of the title compound, M.P. 155 C. dec.

Analysis.Found (percent): C, 63.10; H, 7.25; N, 10.36; Cl, 8.40; S, 7.14. C H ON SCI requires (percent): C, 62.91; H, 7.12; N, 10.00; Cl, 8.44; S, 7.64.

EXAMPLE 4 dl-l7a-chloroethynyl-13-ethyl-17-hydroxygon-4-en-3-one, (4-ethyl-3thiosemicarbazone) A solution of 0.5 g. of dl-17a-chloroethynyl-13-ethyl- 17-hydroxygon-4-en-3-one and 0.2 g. of 4-ethyl-3-thiosemicarbazide in 10 ml. of glacial acetic acid is heated to reflux for 10 minutes. A precipitate forms on cooling and dilution with water. The product is filtered, dissolved in methanol, filtered again and reprecipitated by adding water. Filtration of the product affords 0.4 g. of the title compound, M.P. 17 C. dec.

8. 55;, 3.00, 3.44, 6.15, 6.52 Analysis.--Found (percent): C, 64.15; H, 7.66; N, 9.39;

S, 7.27; CI, 7.98. C H ON SCI requires (percent): C, 64.33; H, 7.65; N, 9.38; S, 7.16; CI, 7.91.

EXAMPLE 5 dl-13-ethyl-17ot-cthynyl-17-hydroxygon-4-ene-3-one, (4-ethyl-3-thi0semicarbazone) A solution of 1.0 g. of dl-l3-ethyl-17a-ethynyl-17-hydroxygon-4-en-3-one and 0.45 g. of 4-ethyl-3-thiosemicarbazide is dissolved in 25 ml. of glacial acetic acid. The solution is refluxed for 10 minutes. On cooling, a precipitate forms which was filtered and Washed with water. The product is dried at C. over P 0 and KOH to obtain 0.95 g. of the title compound, M.P. 230-232 C.,

A5,; 2.96, 3.12, 3.50, 6.18, 6.59, 6.72 Analysis.--Found (percent): C, 70.13; H, 8.45; N, 9.85; S, 7.88. C H ON S requires (percent): C, 69.70; H, 8.53;N, 10.16; S, 7.74.

EXAMPLE 6 dl-13-ethyl-17ot-ethynyl-l7-hydroxygon-4-en-3-one (4-methyl-3-thi0semicarbazone) The procedure of Example 5 is repeated, substituting 4- methylthiosemicarbazide for 4-ethylthiosemicarbazide and the product is obtained.

EXAMPLE 8 dl-l 3-ethyl-17ot-ethynyl-17a-hydroxygon-4-en-3-one, (4-butyl-3-thiosemicarbazone) The procedure of Example 5 is repeated, substituting 4-butylthiosemicarbazide for 4-ethylthiosemicarbazide and the product is obtained.

EXAMPLE 9 dl-l3-ethyl-l7a-ethynyl-l7-hydroxygon-4-en-3-one, (4-hepty1-3-thiosemicarbazone) The procedure of Example 5 is repeated, substituting 4- heptylthiosemicarbazide for 4-ethylthiosemicarbazide and the product is obtained.

EXAMPLE 10 dl-13-ethyl-l7u-ethynyl-17-hydroxygon-4-en-3-one, (4-phenyl-3-thiosemicarbazone) The procedure of Example 5 is repeated substituting 4- phenylthiosemicarbazide for 4-ethylthiosemicarbazide and the product is obtained.

EXAMPLE 1 l dl-13-ethyl-17a-ethynyl-l7-hydroxygon-4-en-3-one, (4-benzyl-3-thiosemicarbazone) The procedure of Example 5 is repeated substituting 4- benzylthiosemicarbazide for 4-ethylthiosemicarbazide and the product is obtained.

EXAMPLE l2 dl-l3-ethyl-l7a-ethynyl l7 hydroxygon-4-en-3-one, (4aphenylethyl-3 -thiosemicarbazone The procedure of Example 5 is repeated substituting 4u-phenylethylthiosemicarbazide for 4-ethylthiosemicarbazide and the product is obtained.

7 EXAMPLE 13 dl-13 ethyl-17a-ethynyl-17-hydroxygon-4-en-3-one, (4-0- tolyl-3-thiosemicarbazone) The procedure of Example is repeated substituting 4-o-tolylthiosemicarbazide for 4-ethylthiosemicarbazide and the product is obtained.

EXAMPLE 14 dl-13-ethyl-17a-ethyny1-17-hydr0xygon-4-en-3-one, (4-ptolyl-S-thiosemicarbazone) The procedure of Example 5 is repeated substituting 4-ptolylthiosemicarbazide for 4-ethylthiosemicarbazide and the product is obtained.

EXAMPLE The procedure of Example 6 is repeated substituting for the dl-13-ethyl-17a-ethynyl 17 hydroxygon-4-en-3-one, stoichiometrical amounts of the following 3-ketosteroids:

d-17a-ethyny1- 17 -hydroxyestra-4,9, 1 1-trien-3-one, acetate;

d-17a-chloroethynyl-17-hydroxyestra-4,9,1 1-trien-3-one;

d-1a,7a-dimethyl-17a-ethynyl 17 hydroxyestr-4-en-3- one;

d-17a-ethynyl-17-hydroxy-4-methylestr-4-en-3-one;

d l- 1 7a-ethynyl- 17-hydroxyestra-4,8 14) -dien-3 -one;

d-l7a-ethynyl-17-hydroxyestra-4,9-dien-3-one;

d-l7a-ethynyl-17-hydroxyestr-4,9,11-trien-3 -one;

d-17a-ethynyl-17-hydroxy-1 1fi-methylestr-4-en-3-one;

d-l7a-chloroethynyl-17-hydroxyestra-4,9-dien-3-one;

dl-13-ethyl 17oz ethynyl 17 hydroxygon-4-en-3-oneacetate;

dl-13-ethyl 17a ethynyl 17 hydroxygon-4-en-3-one, n-heptanoate;

(ll-17am chloroethynyl-13-ethyl-17a-hydroxy-D-homogon-4-en-3-one;

dl-17/3 hydroxy-13-n-propy1-17-(1-propynyl)gona-4,9- dien-3-one;

dl-13-ethyl-17aa-ethynyl 17a hydroxy-D-homogon-4- en-3-one;

dl 13-ethyl-17a-ethynyl-17-hydroxygona-4,8(14)-dien- 3-one;

dl-13-ethyl-17a-ethynyl 17 hydroxy-6a-methylgon-4- en-3-one;

al 13-ethyl-17a-ethynyl-17-hydroxygon-4,6-dien-3-one, acetate;

l-17a-chloroethynyl 13 ethyl-17-hydroxygon-4-en-3- one;

dl-17a-ethynyl-17-hydroxyestr-4-en-3-one, acetate;

a'l-17a-ethynyl 17 hydroxy-13-n-propylgona-4,9-dien- 3-one; and

dl-l3-n-butyl-17a-ethyny1-17-hydroxygon-4-en-3-one.

The following compounds are obtained:

a' 17a-ethyny1-17-hydroxyestra-4,9,11-trien-3-one, acetate, thiosemicarbazone;

d-17a-chloroethynyl 17 hydroxyestra-4,9,11-trien-3- one, thiosemicarbazone;

d-1a,7a-dimethyl-17a-ethynyl 17 hydroxyestr-4-en-3- one, thiosemicarbazone;

d-17u-ethynyl 17 hydroxy-4-methylestr-4-en-3-one, thioseniicarbazone;

dl-17a-ethyl 17-hydroxyestra-4,8(14)-dien-3-one, thiosemicarbazone;

d-17a-ethynyl 17 hydroxyestra 4,9-dien-3-one, thiosemicarbazone;

d-17oc ethynyl-l7-hydroxyestr-4,9,11-trien-3-one, thiosemicarbazone;

d-17a-ethynyl 17 hydroxy-l lp-methylestr-4-en-3-one, thiosemicarbazone;

d-17a-chlor0ethynyl 17 hydroxyestra-4,9-dien-3-one, thiosemicarbazone;

dl-13-ethyl 17cc ethynyl 17 hydroxygon-4-en-3-oneacetate, thiosemicarbazone;

dl-13-ethyl 17oz ethynyl-17-hydroxygon-4-en-3-one, nheptanoate, thiosemicarbazone;

dl-17au-ch1oroethynyl 13 ethyl-l7a-hydroxy-D-homogon-4-en-3-one, thiosemicarbazone;

dl-17B-hydroxy 13 n propyl-17-(1-propynyl)gona- 4,9-dien-3-one, thiosemicarbazone;

dl-13-ethyl-17aa-ethynyl 17a hydroxy-D-homogon-4- en-3-one, thiosemicarbazone;

dl-13-ethyl-17a-ethynyl 17 hydroxygona-4,8(14)- dien-3-one, thiosemicarbazone;

dl-13-ethyl 17a ethynyl 17 hydroxy-6a-methylgon- 4-en-3-one, thiosemicarbazone;

dl-13-ethyl 17m ethynyl 17 hydroxygon-4,6-dien-3- one, acetate, thiosemicarbazone;

l-17a-chloroethynyl 13 ethyl-17-hydroxygon-4-en-3- one thiosemicarbazone;

dl-17a-ethynyl 17 hydroxyestr-4-en-3-one, acetate, thiosemicarbazone;

dl-17a-ethynyl 17 hydroxy-13-npropylgona-4,9-dien- 3-one, thiosemicarbazone; and

dl-13-n-butyl 17a ethynyl 17 hydroxygon-4-en-3- one, thiosemicarbazone.

EXAMPLE 16 d l-13,l7u-diethyl-17-hydroxyg0n-4-en- 3-one, thiosemicar-bazone A solution of 1.26 g. of dl-13,17u-diethyl-17-hydroxygon-4-en-3-one, 0.364 g. of thiosemicarbazide, ml. of alcohol, 10 ml. of acetic acid is refluxed for two hours. The reaction mixture is diluted with 300 ml. of water and the resulting precipitate is collected to give 1.1 g. of the title compound; M.P. 163-164 C.

Analysis.Found (percent): C, 67.29; H, 8.84; N, 10.53; S, 8.55. C H N OS requires (percent): C, 67.82; H, 9.06; N, 10.73; S, 8.23.

EXAMPLE 17 d-17-hydroxy-17u-ethynylestra-4-en- 3-one, semicarbazone A suspension of 1.0 g. of d-l7-hydroxy-l7u-ethynylestr-4-en-3-one, 1.0 g. of sodium acetate (anhydrous), 1.0 g. of semicarbazide hydrochloride, 12.5 ml. of alcohol, and 15 ml. of water is refluxed for 4 hours. The reaction mixture is diluted with water and the resulting precipitate is filtered to give 0.7 g. of the title compound; M.P. 200 C. dec.

Analysis.--Found (percent): C, 70.78; H, 8.09; N, 11.53. C H N O requires (percent): C, 70.95; H, 8.22; N, 11.82.

EXAMPLE 18 EXAMPLE 19 d-17a-ethynyl-17-hydroxyestr-4-en-3-one, (4-ethyl-3-thiosemicarbazone) A solution of 1 g. of d-l7ot-ethynyl-17-hydroxyestr-4- en-3-one and 0.41 g. of 4-ethyl-3-thiosemicarbazide in 25 ml. of glacial acetic acid is heated to reflux for minutes. After cooling, the solution is diluted with water, and the resulting precipitate is filtered off and washed with water. The solid material is crystallized from 60 ml. of methanol to obtain 0.78 g. of flakes identified to be the title compound, M.P. 229232 C., dec.,

Analysis-Found (percent): C, 69.03; H, 8.34; N, 10.54; S, 8.23. C H ON S requires (percent): C, 69.13; H, 8.32; N, 10.52; S, 8.02.

EXAMPLE d-17a-ethynyl-17-hydroxyestr-4-en-3-one, (4-methyl-3-thiosemicarbazone) A solution of 1 g. of d-17a-ethynyl-17-hydroxyestr-4- en-3-one and 0.36 g. of 4-methylthiosemicarbazide in 25 ml. of glacial acetic acid is heated to reflux for 10 minutes. After cooling, the solution is diluted with water, and the resulting precipitate is filtered OE, and washed with water. The solid material is crystallized from 60 ml. of methanol to obtain 0.65 g. of flakes identified to be the title compound, M.P. 239242 C., dec.,

Analysis.--Found (percent): C, 68.41; H, 7.75; S, 8.81; N, 10.77. C H OSN requires (percent): C, 68.53; H, 8.10; S, 8.32; N, 10.90.

In evaluating the instant compounds for pharmacological activity, they are tested in vivo by standard methods with the following results.

Anti-inflammatory screening and evaluation.Antiinflammatory activity of a compound is assessed by its ability to inhibit experimentally-induced edema in the hind paw of the rat [Winter et al., Proc. Soc. Exp. Biol. and Mid., 111, 544 (1962) and Buttle et al., Nature, 179, 629 (1957)]. Male Sprague-Dawley rats 120-165 grams are used. Compound is administered perorally as a solution or suspension in distilled water (plus 2 drops of polyoxyethylene sorbita'n monooleate) in a volume of 10 mL/kg. Each compound is given to 6 rats and vehicle alone is administered to 6 more rats as a control. One hour after drug administration edema is induced by an injection of 0.05 ml. of a 1% carrageenin solution in max.

10 saline into the subplantar tissue of the rats right hind paw. Paw volume is then immediately measured volumetrically with a plethysmograph and again 3 hours later. The mean volume of swelling for the control group is calculated and compared to the test groups. Compounds that inhibit swelling approximately 26% as compared to controls are considered active.

In this test, 12-ethyl-17wethyny1-17-hydroxygon-4-en- 3-one, thiosemicar-bazone administered p.o. at 50 mg./kg., induced a 28 percent inhibition and was active.

Bronchodilator screening and evaluation.The bronchodilator activity of a compound is determined by its ability to protect a guinea pig against the bronchoconstrictor effects of a histamine mist [Modification of Seigmund et al., J. PharmacoL, 90, 254 (1947); 97, 14 (1949)]. A 0.2% (base) histamine diphosphate solution is atomized and sprayed into a closed chamber for 60 seconds. The guinea pig is then placed into the chamber and observed for asphyxial effects. When convulsions are imminent, the pig is removed from the chamber and allowed to recover. The time from placing the pig in the chamber until convulsions are imminent is recorded and is designated pro-convulsion time. Five pigs are used per compound and control times are obtained for each pig in the morning. Only pigs having control times in the range of 50-100 seconds are used in the test. After a 3 /2 to 4 hour recovery period the pigs are administered compound intraperitoneally and 15 minutes later are again exposed to the histamine aerosol. An animal that can withstand 3 times its morning preconvulsion time is considered completely protected. Individual control (C) and post drug preconvulsion times (T) are recorded and an activity value calculated by the formula, (T/ C A mean (T/C) value greater than 1.5 indicates activity.

In this test, 13-ethyl-17u-ethynyl-17-hydroxygon-4-en- 3-one, thiosemicarbazone, administered at 25 and 50 mg./kg. caused a T/C, respectively, of 2.01 and 2.42, and was active; and l-l3-ethyl-17a-ethylnyl-17-hydroxygon-4-en-3-one, thiosemicarbazone, administered at 25 and 50 mg./kg. caused a T/C, respectively, of 1.61 and 2.52, and was active. It is noteworthy that the last named compound is devoid of progestational activity in the Clauberg test [Procedure, Elton and Edgren, Endocrinology, 63, 464 (1958)].

We claim:

1. A compound of the formula wherein X is O or S;

Y is alkyl or --CECR2 wherein R is hydrogen, methyl,

chloro, bromo or fluoro;

R is alkyl;

R is hydrogen or alkanoyl;

R R R R R and R are hydrogen or methyl;

R is hydrogen, alkyl, monocarbocyclic aryl, monocarbocyclic arylalkyl or alkylrnonocarbocyclic aryl;

n is 1 or 2; the broken lines indicate a single or double bond and said alkyl and alk-anoyl substituents contain from about 1 to about 7 carbon atoms.

2. A gon-4-ene compound as defined in claim 1 wherein X is S; Y is CECH, R is ethyl, R R R R R R R and R are hydrogen and n is 1.

3. A compound as defined in claim 2 in the form of its l-enantiomer, substantially free of its d-enantiomer.

4. A gon-4-ene compound as defined in claim 1 wherein X is S; Y is -CECH, R is methyl, R R R R R, R", R and R are hydrogen and n is 1.

5. A gon-4-ene compound as defined in claim 1 wherein X is S; Y is CECC1, R is ethyl, R R R R R R, R and R are hydrogen and n is 1. V

6. A gon-4-ene compound as defined in claim 1 wherein X is S; Y is CECC1, R and R are ethyl, R R R R R, R and R are hydrogen and n is 1.

7. A g0n-4-ene compound as defined in claim 1 wherein X is S; Y is CECH, R and R are ethyl, R R R R R, R and R are hydrogen and n is 1.

8. A gon-4-ene compound as defined in claim 1 wherein 5 R R and R are hydrogen; R is methyl and n is 1.

X is S; Y and R are ethyl, R R R R R R, R 15 References Cited FOREIGN PATENTS 651,797 2/1965 Belgium 260-397.4 1,041,279 9/1966 Great Britain 260-397.4 1,043,018 9/1966 Great Britain 260-3974 OTHER REFERENCES Djerassi, Steroid Reactions (1963), pp. 62-63 relied on.

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 260397.45, 397.4 

